Delayed Recognition of Intrathecal Methotrexate Overdose Baris Malbora, MD,* Emel Ozyurek, MD,* Aysu Inan Kocum, MD,w and Namik Ozbek, MD* Summary: A 10-year-old girl who presented to our hospital was diagnosed as having B-precursor cell acute lymphoblastic leukemia. St Jude’s Total XIII protocol was started. In the second block of the consolidation phase, 10 hours after triple intrathecal treatment, we realized that instead of 12 mg, 120 mg of methotrexate had accidentally been given. Although the patient had no symptoms 10 hours after intrathecal treatment, to prevent the possible neuro- toxic effects of methotrexate, a cerebrospinal fluid exchange was performed. Simultaneously, systemic dexamethasone and calcium folinic acid were given. At the time of this writing (2 y), the patient has had no symptoms and has continued on the chemotherapy protocol as planned. Administration of high-dose intrathecal methotrexate may not lead to symptoms, as was the case in our patient. This may be related to individual variations in cerebrosp- inal fluid dynamics and drug metabolism. Key Words: acute lymphoblastic leukemia, children, intrathecal methotrexate, neurotoxicity, overdose (J Pediatr Hematol Oncol 2009;31:352–354) M ethotrexate is a chemotherapeutic agent used to treat acute lymphoblastic leukemia and lymphoma. Besides the oral and parenteral routes, the drug also can be administered intrathecally as prophylaxis or therapy for central nervous system involvement. Methotrexate is a well-known neurotoxic agent, causing acute and transient focal cerebral dysfunction, reversible posterior leukoencepha- lopathy, acute meningoencephalitis, subacute encephalomye- lopathy, and chronic progressive encephalopathy. 1–3 One of the rare, but potentially lethal adverse effects of methotrexate is intrathecal overdose. 4–10 Current therapy approaches for high-dose intrathecal methotrexate intoxications include removal of cereb- rospinal fluid (either by drainage, exchange, or ventri- culolumbar perfusion), intrathecal administration of carboxypeptidase G 2 , and systemic and/or intrathecal corticosteroid and leucovorin administration. 4–12 Here, we present the case of a 10-year-old girl with intrathecal methotrexate overdose. CASE REPORT A 10-year-old girl who presented to our hospital was diagnosed as having B-precursor cell acute lymphoblastic leukemia. At diagnosis, there was no involvement of the central nervous system or other extramedullary sites. St Jude’s Total XIII Study Protocol was started. 13 She underwent remission induction treatment that included 2 triple intrathecal therapies (12 mg of methotrexate, 20 mg of prednisolone, and 36 mg of cytosine arabinoside) without any complications. Consequently, after her remission, she was hospitalized for consolidation treatment consisting of triple intrathecal therapy and high-dose methotrexate infusion (2 g/m 2 /d). During hospitalization, her weight was 30 kg (25th percen- tile) and her height was 145 cm (90th percentile). The results of a physical examination were normal. The patient’s complete blood count revealed a white blood cell count of 8.7  10 9 /L with a differential including 28% neutrophils, 13% monocytes, and 59% lymphocytes; a hemoglobin level of 8.4 g/dL; and a platelet count of 128  10 9 /L. Serum blood urea nitrogen, creatinine, sodium, potassium, calcium, phosphorus, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, total bilirubin, and direct bilirubin levels were within normal limits. According to the protocol, triple intrathecal treatment was ordered for the patient. She underwent intrathecal therapy under sedative anesthesia in the operating room. During and immediately after therapy, she was monitored closely for complications of anesthesia. Immediately after treatment, intravenous high-dose methotrexate was started. Ten hours after intrathecal treatment, while preparing for the second part of high-dose methotrexate treatment, one of the nurses realized that a 500-mg vial of methotrexate instead of 50-mg vial had been used for intrathecal therapy. Therefore, the patient had received 120 mg methotrexate instead of 12 mg. The intravenous infusion of high-dose metho- trexate was terminated immediately. Although the patient did not have any symptoms, to prevent the possible neurotoxic adverse effects of methotrexate, a lumbar catheter was placed into the subarachnoid space, and 12 mL/h cerebrospinal fluid exchange was started with warmed isotonic saline (3 mL in every 15 min). The first cerebrospinal fluid obtained was yellow in color, and then the color became clear. We exchanged 72 mL cerebrospinal fluid (50% of the estimated total cerebrospinal fluid volume) with isotonic saline. Simultaneously, each of the following was given for a total of 4 doses every 6 hours: high-dose calcium folinic acid (40 mg/m 2 / dose IV) and dexamethasone (0.15 mg/kg/dose IV). An electroencephalograph performed in the 24th hour of intrathecal treatment revealed a disturbed background rhythm shown as a slow activation increase and paroxysmal activation in the right temporal region. Because the patient did not have any symptoms, anticonvulsant therapy was not started. Instead, the patient was followed closely in the hospital for 5 days. At the end of the fourth day, intravenous cyclophos- phamide and VP-16 treatments, which comprised the first week’s therapy of St Jude’s Total XIII maintenance, were administrated without complications. At the time of this writing, the patient is in remission and is well without any neurologic sequelae. The results of a control electroencephalograph 1.5 years after overdose were normal. At the time of this writing, she is in her 103rd week treatment of maintenance therapy. DISCUSSION Intrathecal methotrexate overdose is a rare, but frequently lethal, toxicity, and its management is not clear. 11 Experiences from new cases may add insight to Copyright r 2009 by Lippincott Williams & Wilkins Received for publication August 12, 2008; accepted October 11, 2008. From the Departments of *Pediatric Hematology; and wAnesthesiology and Reanimation, Baskent University Faculty of Medicine, Ankara, Turkey. Reprints: Baris Malbora, MD, Department of Pediatrics, Baskent University Faculty of Medicine, 6. Cadde, No: 72/3, Bahcelievler 06490, Ankara, Turkey (e-mail: barismalbora@gmail.com). CLINICAL AND LABORATORY OBSERVATIONS 352 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 31, Number 5, May 2009